These UPDATES were a project of Pain Treatment Topics; Stewart B. Leavitt, MA, PhD, publisher/editor. Our mission was to serve as a noncommercial resource for healthcare professionals & their patients, providing open access to clinical news, information, research, and education with a focus on better understandings of evidence-based pain-management practices. New postings and comments were discontinued as of January 2014.

Wednesday, August 8, 2012

A recent Citizen Petition to the United States Food and Drug Administration (FDA) by Physicians for Responsible Opioid Prescribing, or PROP, requests labeling changes for all opioid analgesics when it comes to their prescription for noncancer pain. The changes would limit the dose, impose time limits, and restrict opioid use for only severe pain.

The Petition raises some important questions about the safety and efficacy of opioid analgesics as they are currently FDA-approved and prescribed. And, the urgency of an investigation was heightened by the fact that a Congressional committee has joined the petitioners in demanding action from the FDA. But, a critical question is whether there is sufficient evidence of reasonable quality for the FDA to act on the Petition at this time.

A Crisis of Confidence in Evidence

At every turn these days, opioid analgesics seem to be on trial, whether in the court of public opinion fueled by mass media, in the U.S. Congress and state legislatures, in various government agencies, and among select groups of healthcare professionals. Yet, what may be most at stake here is a crisis of confidence in scientific methods of inquiry and the reliance on valid research evidence as proof when it comes to making judgments that guide clinical practice in pain management.

Since our inception in late 2005, the mission of Pain Treatment Topics has been to focus on principles of evidence-based pain management. In Part 11 of our ongoing series, “Making Sense of Pain Research” [here], we examined several questions: What qualifies as evidence? What are the requirements of evidence as proof? How much proof is necessary for reaching valid and just clinical decisions?

We reminded readers, “Just as juries need good evidence to reach prudent verdicts, healthcare providers need good evidence as a guide for better decision-making in treating patients with pain.” However, due to the nature of scientific inquiry and research methods, absolute certainty is an illusion and research outcomes must be used circumspectly and wisely for reaching judicious conclusions affecting patients’ health and well-being.

We say all of this because, as much as anything, the PROP Petition [available here] raises questions about how pain research evidence could and should be interpreted and used for influencing decision-making and change. And, it also raises questions regarding the quality, quantity, relevance, and validity of evidence necessary for establishing an acceptable level of proof in pain management.

In previous UPDATES, we have dissected, discussed, and/or challenged much of the evidence that is used in the PROP Petition to support their requested changes to opioid-product labeling. This and additional evidence also is discussed in a recent guest author UPDATE [here] by Bob Twillman, PhD, FAPM, and further opinions debating claims of the Petition are offered elsewhere by clinical pharmacy specialist, Jeffrey Fudin, RPh, PharmD, DAAPM, FCCP [here].

In short, there does not appear to be a body of good, clear, and convincing evidence at this time to support the requests in the Petition, let alone any evidence beyond reasonable doubt for passing judgment. However, this is not to say that the petitioners’ assertions are frivolous or unworthy of further investigation and discussion.

We should note that commenting is not limited to Americans, and persons from all parts of the world may have much at stake here. Changes to opioid labeling and prescribing in the U.S. may inspire other countries to re-examine how these medications should best be prescribed in their own populations. We would encourage any and all persons with something to say on this matter, pro or con, to submit a comment.

Here is the text of the public comment letter that we submitted to the FDA on August 6, 2012; Tracking ID# 810c2f4b….

On July 25, 2012, Physicians for Responsible Opioid Prescribing (PROP) and allied signatories submitted a Citizen Petition to the U.S. Food and Drug Administration (FDA) requesting certain changes to opioid analgesic labeling. These would limit opioid dosing, impose time limits, and restrict opioid use in noncancer conditions to only severe pain.

The Petition appears to be most concerned with opioid analgesia for chronic noncancer pain, and excludes cancer-related pain, but there is some confusion as to whether the label changes would apply also to acute pain. In any event, it seems that the broad and implicit hypothesis underlying the Petition might be stated as this:

Compared with opioid analgesic prescribing practices following indications on current product labeling, patients would be afforded superior effectiveness and safety if opioids were restricted to a dose of ≤100 mg/day of morphine or its equivalent for no more than 90 continuous days and only for severe pain in the case of noncancer conditions.

If this hypothesis is true, countless patients are possibly being mistreated or harmed by current prescribing practices, and it would be important to know if any or all of the Petition’s recommendations should be adopted. As it presently stands, however, there are some serious concerns regarding acceptance of the Petition and its implicit hypothesis:

The hypothesis has not been directly tested by adequate, prospective clinical research trials of any quality or sufficient quantity.

Current best evidence submitted by the petitioners under their “Statements of Scientific Basis for Petition” has been challenged in terms of its relevance, adequacy, and/or validity [Twillman 2012, ref below].

Limited clinical evidence presented at a recent FDA-sponsored Workshop last May, 2012, to assess analgesia for chronic pain was largely of lower quality — observational or epidemiological — and generally equivocal or inconclusive regarding the absolute benefits vs risks of long-term opioid therapy at any dose for various types of pain conditions [FDA 2012].

Therefore, the Petition proposes a hypothesis that raises important questions but, in itself, is untested and unproven. And, it seems apparent that, at this time, changing opioid-product labeling in accordance with the Petition’s requests could be tantamount to enrolling millions of persons with pain — unknowingly and non-consenting — as participants in a clinical experiment to test an unfounded medical theory.

Certainly, the clinical, scientific, ethical, and legal implications of this are daunting, and memory of egregiously cruel human experiments in history would seem to preclude the labeling change at present. Unintended consequences of the label change could possibly be significantly adverse and harsh.

Still, in the court of scientific inquiry there seems sufficient evidence for reasonable suspicion that some, if not all, of the Petition’s perspectives could merit further investigation. Government research-oriented agencies might be encouraged to examine these issues further and to fund the necessary well-designed clinical investigations.

First, however, it would be necessary to operationally define what is specifically meant in the Petition by such terms as: safety, effectiveness, noncancer, and severe pain. And, to better justify for testing the assignation of ≤100 mg/day morphine or equivalent and 90 days duration as threshold points.

Surely, opioid analgesics are not the only or best solution for all types of pain, whether acute or chronic, cancer or noncancer, and in all patients. Ultimately, the goal is to afford patients the best possible pain management, and to identify those patients who might benefit most from opioid analgesia at any dose and/or for any length of time.

Our purpose in commenting was not to challenge particular research referenced in the Petition or the specifically requested changes; rather, to address issues of scientific method and the uses of evidence as proof. Quite simply, a new clinical hypothesis requires some basis in science or prior evidence to justify testing — which might be met by the limited evidence cited in the Petition — but the hypothesis itself should not be not put into practice until it has been tested and proven valid. Essentially, if opioid labeling were changed at this time in accordance with the Petition it would be “putting the cart before the horse” from an evidence-based medicine perspective.

In his recent guest author Pain-Topics UPDATE, Dr. Twillman, PhD, FAPM, did a thorough job of discussing and questioning the evidence base behind the Petition. In fair balance, immediately after we posted the Twillman UPDATE, we alerted Andrew Kolodny, MD, of the article; he is president of PROP and a principal signer of the Petition. We extended to Dr. Kolodny, and any fellow cosigners of the Petition, an open invitation to submit for publication a rebuttal UPDATE article commenting on Twillman’s critique and/or further presenting their own perspectives. [ADDENDUM: Dr. Kolodny did respond to us later today: available here.]

Congress Embraces the Petition

On July 26, 2012 — just one day after the Petition was filed with the FDA — Congresswoman Mary Bono Mack and 5 fellow members of the Congressional Caucus on Prescription Drug Abuse sent a public letter [available here] to Margaret Hamburg, MD, FDA Commissioner, essentially endorsing the Petition and embracing all of its recommended labeling changes. The letter concludes:

“We believe that if a labeling change were made to opioid analgesics to reflect the uncertainty and lack of evidence surrounding safety and effectiveness of these drugs for treatment of chronic non-cancer pain, physicians would think twice before prescribing these highly addictive narcotics for ‘moderate’ pain such as a toothache or sore knee. While those who seek treatment for cancer pain and other diseases that cause “severe” pain would not be affected, the number of individuals prescribed opiate painkillers without evidence of the long-term safety and effectiveness may decrease and limit those susceptible to developing opioid dependence.”

To our knowledge, none of these elected officials has extensive medical training or expertise in the assessment of research evidence. Their statement reflects some bias in the use of emotion-laden terms — eg, “highly addictive narcotics” and “painkillers” [discussed previously in an UPDATE here] — and, they appear to advocate against even the short-term use of opioids for acute pain, such as a toothache, which is an unclear aspect of the Petition. The Caucus members also seem to have accepted the false argument of the petition, that a lack of evidence is, in itself, acceptable evidence for advocating against the long-term effectiveness and safety of opioids for noncancer pain.

Still, this letter commands the attention of the FDA, since it ends with, “For these reasons, we request an expedited review of the Citizen Petition submitted to FDA, and look forward to a timely response.”

What Happens Now?

In fairness, the letter from Congresswoman Mack and colleagues was merely instructing the FDA to look into the matter and report back. The FDA already held a Workshop last May exploring analgesia for chronic pain, but this letter probably motivated the agency to accept and post the Petition at the government regulations website on July 30, 2012, for further public comment. Again, that site can be accessed [here].

We have from time to time been critical of the FDA; yet, we know that the agency performs a vital function and is staffed with well-trained and dedicated physicians and scientists. They understand the ins and outs of pain research and are unlikely to be swayed by low-quality, biased, or inadequate evidence.

In our opinion, there is more at stake here than the fate of opioid analgesics prescribed for chronic noncancer pain. Conflicts of dogma versus science are at the core of many practices in the pain management field; yet, low-quality evidence and fallacies of logical thinking sometimes appear to be winning the battle.

Furthermore, some of the nuances and ramifications of the petitioned label change must be considered:

Some have argued that changing the label would stop pharmaceutical companies from promoting opioids for uses beyond the new, more limited indications, but, if deemed necessary, practitioners could still prescribe the medications off-label at any dose and for any duration of time in noncancer pain.

However, off-label applications of medications are usually discouraged and can be risky; prescribers know that they could face regulatory scrutiny or liability issues if something goes wrong and they have not followed FDA-approved indications on labeling. The Congressional Caucus members are aware of this when they state, “…physicians would think twice before prescribing these highly addictive narcotics.”

This further raises the question of addiction to opioid analgesics among legitimate patients with pain. Evidence regarding this is discussed by Twillman in his UPDATE, and this still appears to be an unresolved issue needing further definition, investigation, and clarification. Yet, the Caucus members seem to accept the notion that restricting opioid prescribing, “may decrease and limit those susceptible to developing opioid dependence.” By dependence, we presume they mean “addiction” here, rather than the physiological dependence on opioids that naturally develops in many cases; although, whether or not they fully understand the distinctions seems unknown.

In reaction to the Petition, some professionals have questioned whether public and private healthcare insurance plans would continue to pay for opioid prescriptions that did not adhere to new restrictions indicated on labeling. If not, patients with chronic pain would need to personally absorb the financial burden associated with off-label opioid prescribing, which in many or most cases could preclude or curtail their ongoing access to these medications. Any answers to insurance coverage questions at this time would be speculative.

Most worrying are questions not even raised and addressed in the Petition or by Congressional Caucus members. What should take the place of opioid analgesics for chronic noncancer pain? What are the better, safer, tried and proven therapies?

There are no easy answers to questions and evidentiary dilemmas posed by the Petition. Our own recommendation is that, if the Petition is to be serously considered and judged, there first must be an objectively thorough review and critical assessment of all relevant evidence regarding this issue — pro and con. And, hopefully, these inquiries and further dialogue will be fair-balanced and steered by science — embracing principles of evidence-based medicine — rather than driven by dogma and demagoguery.

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